tbuckley/cabot-search huggingface dataset:
Immunotherapy-induced neutralizing antibodies disrupt allergen binding and sustain allergen tolerance in peanut allergy
Authors: Nicole A. LaHood, Jungki Min, Tarun Keswani, Crystal M. Richardson, Kwasi Amoako, Jingjia Zhou, Orlee Marini-Rapoport, Hervé Bernard, Stéphane Hazebrouck, Wayne G. Shreffler, J. Christopher Love, Anna Pomes, Lars C. Pedersen, Geoffrey A. Mueller, Sarita U. Patil
Journal: Journal of Clinical Investigation (2023)

In IgE-mediated food allergies, exposure to the allergen activates systemic allergic responses. Oral immunotherapy (OIT) treats food allergies through incremental increases in oral allergen exposure. However, OIT only induces sustained clinical tolerance and decreased basophil sensitivity in a subset of individuals despite increases in circulating allergen-specific IgG in all treated individuals. Therefore, we examined the allergen-specific antibodies from 2 OIT cohorts of patients with sustained and transient responses. Here, we compared antibodies from individuals with sustained or transient responses and discovered specific tolerance-associated conformational epitopes of the immunodominant allergen Ara h 2 recognized by neutralizing antibodies. First, we identified what we believe to be previously unknown conformational, intrahelical epitopes using x-ray crystallography with recombinant antibodies. We then identified epitopes only recognized in sustained tolerance. Finally, antibodies recognizing tolerance-associated epitopes effectively neutralized allergen to suppress IgE-mediated effector cell activation. Our results demonstrate the molecular basis of antibody-mediated protection in IgE-mediated food allergy, by defining how these antibodies disrupt IgE-allergen interactions to prevent allergic reactions. Our approach to studying the structural and functional basis for neutralizing antibodies demonstrates the clinical relevance of specific antibody clones in antibody-mediated tolerance. We anticipate that our findings will form the foundation for treatments of peanut allergy using neutralizing antibodies and hypoallergens.
Take your mother’s ferry: preimplantation embryo development requires maternal karyopherins for nuclear transport
Authors: Momal Sharif, Laura Detti, Ignatia B. Van den Veyver
Journal: Journal of Clinical Investigation (2023)

The genetic basis of preimplantation embryo arrest is slowly being unraveled. Recent discoveries point to maternally expressed proteins required for cellular functions before the embryonic genome is activated. In this issue of the JCI, Wang, Miyamoto, et al. suggest a critical role for karyopherin-mediated protein cargo transport between oocyte cytoplasm and nucleus. Defective maternal oocyte-expressed human karyopherin subunit α7 (KPNA7) and mouse KPNA2 fail to bind a critical substrate, ribosomal L1 domain-containing protein 1 (RSL1D1), affecting its transport to the nucleus. As shown in embryos of Kpna2-null females, the consequences are disrupted zygotic genome activation and arrest of development. These findings have important implications for diagnosis and treatment of female infertility.
Impact of epigenetic reprogramming on antitumor immune responses in glioma
Authors: Brandon L. McClellan, Santiago Haase, Felipe J. Nunez, Mahmoud S. Alghamri, Ali A. Dabaja, Pedro R. Lowenstein, Maria G. Castro
Journal: Journal of Clinical Investigation (2023)

Epigenetic remodeling is a molecular hallmark of gliomas, and it has been identified as a key mediator of glioma progression. Epigenetic dysregulation contributes to gliomagenesis, tumor progression, and responses to immunotherapies, as well as determining clinical features. This epigenetic remodeling includes changes in histone modifications, chromatin structure, and DNA methylation, all of which are driven by mutations in genes such as histone 3 genes (H3C1 and H3F3A), isocitrate dehydrogenase 1/2 (IDH1/2), α-thalassemia/mental retardation, X-linked (ATRX), and additional chromatin remodelers. Although much of the initial research primarily identified how the epigenetic aberrations impacted glioma progression by solely examining the glioma cells, recent studies have aimed at establishing the role of epigenetic alterations in shaping the tumor microenvironment (TME). In this review, we discuss the mechanisms by which these epigenetic phenomena in glioma remodel the TME and how current therapies targeting epigenetic dysregulation affect the glioma immune response and therapeutic outcomes. Understanding the link between epigenetic remodeling and the glioma TME provides insights into the implementation of epigenetic-targeting therapies to improve the antitumor immune response.
Karyopherin α deficiency contributes to human preimplantation embryo arrest
Authors: Wenjing Wang, Yoichi Miyamoto, Biaobang Chen, Juanzi Shi, Feiyang Diao, Wei Zheng, Qun Li, Lan Yu, Lin Li, Yao Xu, Ling Wu, Xiaoyan Mao, Jing Fu, Bin Li, Zheng Yan, Rong Shi, Xia Xue, Jian Mu, Zhihua Zhang, Tianyu Wu, Lin Zhao, Weijie Wang, Zhou Zhou, Jie Dong, Qiaoli Li, Li Jin, Lin He, Xiaoxi Sun, Ge Lin, Yanping Kuang, Lei Wang, Qing Sang
Journal: Journal of Clinical Investigation (2023)

Preimplantation embryo arrest (PREMBA) is a common cause of female infertility and recurrent failure of assisted reproductive technology. However, the genetic basis of PREMBA is largely unrevealed. Here, using whole-exome sequencing data from 606 women experiencing PREMBA compared with 2,813 controls, we performed a population and gene-based burden test and identified a candidate gene, karyopherin subunit α7 (KPNA7). In vitro studies showed that identified sequence variants reduced KPNA7 protein levels, impaired KPNA7 capacity for binding to its substrate ribosomal L1 domain-containing protein 1 (RSL1D1), and affected KPNA7 nuclear transport activity. Comparison between humans and mice suggested that mouse KPNA2, rather than mouse KPNA7, acts as an essential karyopherin in embryonic development. Kpna2-/- female mice showed embryo arrest due to zygotic genome activation defects, recapitulating the phenotype of human PREMBA. In addition, female mice with an oocyte-specific knockout of Rsl1d1 recapitulated the phenotype of Kpna2-/- mice, demonstrating the vital role of substrate RSL1D1. Finally, complementary RNA (cRNA) microinjection of human KPNA7, but not mouse Kpna7, was able to rescue the embryo arrest phenotype in Kpna2-/- mice, suggesting mouse KPNA2 might be a homologue of human KPNA7. Our findings uncovered a mechanistic understanding for the pathogenesis of PREMBA, which acts by impairing nuclear protein transport, and provide a diagnostic marker for PREMBA patients.
Rethinking classification and categorization of resection extent and its impact on patient survival in glioblastoma: Was Walter Dandy ahead of his time?
Authors: Rupesh Kotecha, Minesh P Mehta
Journal: Neuro-Oncology (2023)

Journal Article Accepted manuscript Rethinking Classification and Categorization of Resection Extent and its Impact on Patient Survival in Glioblastoma: Was Walter Dandy Ahead of His Time? Get access Rupesh Kotecha, MD, Rupesh Kotecha, MD Department of Radiation Oncology, Miami Cancer Institute, Baptist Health South Florida, Miami, FL 33176 USADepartment of Radiation Oncology, Herbert Wertheim College of Medicine, Florida International University, Miami, FL 33199 USA https://orcid.org/0000-0001-6927-0402 Search for other works by this author on: Oxford Academic PubMed Google Scholar Minesh P Mehta, MD Minesh P Mehta, MD Department of Radiation Oncology, Miami Cancer Institute, Baptist Health South Florida, Miami, FL 33176 USADepartment of Radiation Oncology, Herbert Wertheim College of Medicine, Florida International University, Miami, FL 33199 USA Corresponding author's name and complete mailing: Minesh P. Mehta, MD, Department of Radiation Oncology, Miami Cancer Institute, Baptist Health South Florida, 8900 N Kendall Drive, Miami, FL 33176, Phone: 786-596-2000, Email: mineshm@baptisthealth.net Search for other works by this author on: Oxford Academic PubMed Google Scholar Neuro-Oncology, noad013, https://doi.org/10.1093/neuonc/noad013 Published: 16 January 2023 Article history Received: 06 January 2023 Published: 16 January 2023
Metabolically (un)healthy obesity and risk of obesity-related cancers: a pooled study
Authors: Ming Sun, Josef Fritz, Christel Häggström, Tone Bjørge, Gabriele Nagel, Jonas Manjer, Anders Engeland, Emanuel Zitt, Bethany van Guelpen, Pär Stattin, Hanno Ulmer, Tanja Stocks
Journal: JNCI Journal of the National Cancer Institute (2023)

Studies of obesity with or without metabolic aberrations, commonly termed metabolically unhealthy or healthy obesity, in relation to cancer risk are scarce.We investigated body mass index (normal weight, overweight, obesity) jointly and in interaction with metabolic health status in relation to obesity-related cancer risk (n = 23 630) among 797 193 European individuals. A metabolic score comprising mid-blood pressure, plasma glucose, and triglycerides was used to define metabolically healthy and unhealthy status. Hazard ratios (HRs) and multiplicative interactions were assessed using Cox regression, and additive interactions were assessed using the relative excess risk for interaction. All statistical tests were 2-sided.Metabolically unhealthy obesity, with a baseline prevalence of 7%, was, compared with metabolically healthy normal weight, associated with an increased relative risk of any obesity-related cancer and of colon, rectal, pancreas, endometrial, liver, gallbladder, and renal cell cancer (P < .05), with the highest risk estimates for endometrial, liver, and renal cell cancer (HR = 2.55-3.00). Metabolically healthy obesity showed a higher relative risk for any obesity-related cancer and colon (in men), endometrial, renal cell, liver, and gallbladder cancer, though the risk relationships were weaker. There were no multiplicative interactions, but there were additive, positive interactions between body mass index and metabolic health status on obesity-related and rectal cancer among men and on endometrial cancer (P < .05).This study highlights that the type of metabolic obesity phenotype is important when assessing obesity-related cancer risk. In general, metabolic aberrations further increased the obesity-induced cancer risk, suggesting that obesity and metabolic aberrations are useful targets for prevention.
Keratinocytes as drivers of hidradenitis suppurativa inflammation: need for priming
Authors: Evangelos J Giamarellos-Bourboulis
Journal: British Journal of Dermatology (2023)

Journal Article Keratinocytes as drivers of hidradenitis suppurativa inflammation: need for priming Get access Evangelos J Giamarellos-Bourboulis Evangelos J Giamarellos-Bourboulis 4th Department of Internal Medicine ‘Attikon Hospital’, National and Kapodistrian University of Athens, School of Medicine, Greece Correspondence: Evangelos J. Giamarellos-Bourboulis. Email: egiamarel@med.uoa.gr https://orcid.org/0000-0003-4713-3911 Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 188, Issue 3, March 2023, Pages 318–319, https://doi.org/10.1093/bjd/ljac164 Published: 17 January 2023 Article history Received: 22 December 2022 Published: 17 January 2023 Corrected and typeset: 31 January 2023
Runt-related transcription factor-1 ameliorates bile acid–induced hepatic inflammation in cholestasis through JAK/STAT3 signaling
Authors: Liangjun Zhang, Qiong Pan, Lu Zhang, Haihan Xia, Junwei Liao, Xiaoxun Zhang, Nan Zhao, Qiaoling Xie, Min Liao, Ya Tan, Qiao Li, Jinfei Zhu, Ling Li, Shijun Fan, Jianwei Li, Chengcheng Zhang, Shi-Ying Cai, James L. Boyer, Jin Chai
Journal: Hepatology (2023)

Background and Aims: Bile acids trigger a hepatic inflammatory response, causing cholestatic liver injury. Runt-related transcription factor-1 (RUNX1), primarily known as a master modulator in hematopoiesis, plays a pivotal role in mediating inflammatory responses. However, RUNX1 in hepatocytes is poorly characterized, and its role in cholestasis is unclear. Herein, we aimed to investigate the role of hepatic RUNX1 and its underlying mechanisms in cholestasis. Approach and Results: Hepatic expression of RUNX1 was examined in cholestatic patients and mouse models. Mice with liver-specific ablation of Runx1 were generated. Bile duct ligation and 1% cholic acid diet were used to induce cholestasis in mice. Primary mouse hepatocytes and the human hepatoma PLC/RPF/5- ASBT cell line were used for mechanistic studies. Hepatic RUNX1 mRNA and protein levels were markedly increased in cholestatic patients and mice. Liver-specific deletion of Runx1 aggravated inflammation and liver injury in cholestatic mice induced by bile duct ligation or 1% cholic acid feeding. Mechanistic studies indicated that elevated bile acids stimulated RUNX1 expression by activating the RUNX1 -P2 promoter through JAK/STAT3 signaling. Increased RUNX1 is directly bound to the promotor region of inflammatory chemokines, including CCL2 and CXCL2 , and transcriptionally repressed their expression in hepatocytes, leading to attenuation of liver inflammatory response. Blocking the JAK signaling or STAT3 phosphorylation completely abolished RUNX1 repression of bile acid–induced CCL2 and CXCL2 in hepatocytes. Conclusions: This study has gained initial evidence establishing the functional role of hepatocyte RUNX1 in alleviating liver inflammation during cholestasis through JAK/STAT3 signaling. Modulating hepatic RUNX1 activity could be a new therapeutic target for cholestasis.
Letter to the editor: discussing the place of TIPS in noncirrhotic patients with chronic extrahepatic portal vein occlusion (EHPVO)
Authors: Florent Artru, Pierre-Emmanuel Rautou, Alban Denys
Journal: Hepatology (2023)

We read with great interest the study published by Knight et al,1 reporting the first monocentric large series on the treatment by TIPS associated or not with portal vein recanalization (PVR) of extrahepatic portal vein obstruction and chronic mesenteric vein thrombosis in patients without cirrhosis. In this study gathering patients considered as refractory to standard of care therapy, 39 patients were included, technical success was obtained in 100% and was associated with an improvement of the symptoms in 87% of the 30 patients having more than 6 months of follow-up. Primary and overall TIPS patency was observed in 63% and 81% of the patients at 36 months, respectively. Three patients (8%) developed hepatic encephalopathy. We recently published our monocentric experience2 reporting long-term favorable outcomes following portal PVR without TIPS insertion in a similar patient population. Thirty-one patients were included, technical success was obtained 87% and associated with the resolution of symptoms in 78% at 5 years. 5-year primary and secondary patencies were, respectively, 73% and 76% in per-protocol analyses. No hepatic encephalopathy has occurred. The overall similar results obtained using different techniques call for an in-depth comparison of the results of the 2 studies to propose patients the best option in the future. First, based on our data, we identified two situations where combining PVR to TIPS could be useful: (a) in patients with an extensive intrahepatic portal vein stenosis or occlusion (type 3 of Marot classification) since there is not enough outflow after recanalisation to allow for long-term stent patency; (b) in patients with chronic/refractory abdominal pain as the main indication for treatment, since 6/7 of these patients have not reached 5-year primary patency. We would be interested in knowing the results obtained by Knight and colleagues in these specific situations. Second, decision for placing a TIPS on top of a PVR could be influenced by the presence of an increased intrahepatic vascular resistance after PVR. It would thus be interesting to know if Knight and colleagues had had the possibility to measure portal caval gradient after recanalization when they used the splenic route. Finally, we observed in our cohort, however on a limited sample size (n=15), that PVR without TIPS was associated with an improved muscle mass (P=0.007) and decreased spleen volume (P=0.01) at 1 year. It would be therefore interesting to know if similar results were obtained using PVR combined with TIPS. In any case, the publication of these 2 series with 2 different approaches are bringing hope to improve the treatment of a severe and chronic condition affecting young patients still recently considered as in a dead-end situation.
Correction: Macrophage Exclusion after Radiation Therapy (MERT): A First-in-Human Phase I/II Trial using a CXCR4 Inhibitor in Glioblastoma
Authors: Reena P. Thomas, Seema Nagpal, Michael Iv, Scott G. Soltys, Sophie Bertrand, Judith S. Pelpola, Robyn Ball, Jaden Yang, Vandana Sundaram, Sophia B. Chernikova, Jonathan Lavezo, Donald Born, Hannes Vogel, J. Martin Brown, Lawrence D. Recht
Journal: Clinical Cancer Research (2023)

In the original version of this article (1), author Sophia B. Chernikova is mistakenly omitted from the author list. The error has been corrected in the latest online HTML and PDF versions of the article and the author contributions and disclosures have been updated as necessary. The authors regret the error.
Correction: Intraperitoneal Monocytes plus IFNs as a Novel Cellular Immunotherapy for Ovarian Cancer: Mechanistic Characterization and Results from a Phase I Clinical Trial
Authors: Daniel S. Green, Franklin Ning, Anna Duemler, Timothy G. Myers, Kathryn Trewhitt, Irene Ekwede, Ann McCoy, Nicole Houston, Jung-min Lee, Stanley Lipkowitz, Alexandra Zimmer, Miroslava Pavelova, Erin N. Villanueva, Leslie Smith, Andrew Blakely, Yovanni Casablanca, Steven L. Highfill, David F. Stroncek, Naoza Collins-Johnson, Sandhya Panch, JoLynn Procter, Chauha Pham, Soumya Korrapati, Steven M. Holland, Lindsey B. Rosen, Ana T. Nunes, Kathryn C. Zoon, Christopher B. Cole, Christina M. Annunziata
Journal: Clinical Cancer Research (2023)

In the original version of this article (1) as it was published online on September 28, 2022, author Soumya Korrapati is mistakenly omitted from the author list. The HTML and PDF versions of this article were corrected on December 23, 2022, ahead of print and the author contributions and disclosures were updated as necessary. The authors regret the error.
Response letter to Sun et al, re: Pathological collagen targeting and penetrating liposomes for idiopathic pulmonary fibrosis therapy
Authors: Ming-Yuan Yang, Yi-Jun Lin, Meng-Meng Han, Yu-Yang Bi, Xing-Yue He, Lei Xing, Jee-Heon Jeong, Tian-Jiao Zhou, Hu-Lin Jiang
Journal: Journal of Controlled Release (2023)
Letter to the editor: diagnosing fibrosis and cirrhosis in nonalcoholic fatty liver disease using machine learning models
Authors: Yifei Feng, Boshizhang Peng, Yanan Li, Lejia Sun, Yueming Sun
Journal: Hepatology (2023)

To the editor, We read with great interest the article published in Hepatology by Chang et al.1 regarding their machine learning (ML) models that outperformed traditional noninvasive tests in identifing liver fibrosis and cirrhosis in patients with NAFLD. Herein, we discuss some points further. First, the authors selected 17 clinical features to train ML models. Although serum biomarkers, including type IV collagen2 and procollagen III,3 are strongly associated with fibrosis in NAFLD, they were not included. Adding these biomarkers to the model may improve its performance. Additionally, other known variables associated with NAFLD, including serum creatinine and uric acid, may be incorporated with selected features to develop ML models. Second, only a portion of patients underwent liver biopsy, which implies that the reference standard for fibrosis stages of other patients were noninvasive tests, including FibroScan and Fibrosis-4 index. However, the ML models were compared with these tests to highlight their efficiency. It would be more convincing if the predictive accuracy of ML models were more accurate than those of other noninvasive tests in the liver biopsy subgroup. Third, the authors found that the random forest model performed the best in predicting fibrosis in patients with NAFLD; however, a newly developed algorithm, called extreme gradient boosting (XGboost), is widely recognized for its accuracy. For instance, in Knowlegde Discovery and Data Mining Cup 2015, the top-10 winning teams all used XGBoost algorithm.4 Therefore, it would be intriguing to examine whether XGboost can further highlight the advantages of ML models in this research. Finally, ethnic differences affect NAFLD;5 thus, further validation is required before this American-based model can be applied to other races. Nevertheless,>we appreciate the authors' work as the study offers a novel and effective tool for physicians to identify fibrosis in patients with NAFLD, while considering the limitations of traditional diagnostic tools.
Valency and affinity control of aptamer-conjugated nanoparticles for selective cancer cell targeting
Authors: Laura Woythe, David Porciani, Tessa Harzing, Stijn van Veen, Donald H. Burke, Lorenzo Albertazzi
Journal: Journal of Controlled Release (2023)

Nanoparticles (NPs) are commonly functionalized using targeting ligands to drive their selective uptake in cells of interest. Typical target cell types are cancer cells, which often overexpress distinct surface receptors that can be exploited for NP therapeutics. However, these targeted receptors are also moderately expressed in healthy cells, leading to unwanted off-tumor toxicities. Multivalent interactions between NP ligands and cell receptors have been investigated to increase the targeting selectivity towards cancer cells due to their non-linear response to receptor density. However, to exploit the multivalent effect, multiple variables have to be considered such as NP valency, ligand affinity, and cell receptor density. Here, we synthesize a panel of aptamer-functionalized silica-supported lipid bilayers (SSLB) to study the effect of valency, aptamer affinity, and epidermal growth factor receptor (EGFR) density on targeting specificity and selectivity. We show that there is an evident interplay among those parameters that can be tuned to increase SSLB selectivity towards high-density EGFR cells and reduce accumulation at non-tumor tissues. Specifically, the combination of high-affinity aptamers and low valency SSLBs leads to increased high-EGFR cell selectivity. These insights provide a better understanding of the multivalent interactions of NPs with cells and bring the nanomedicine field a step closer to the rational design of cancer nanotherapeutics.